Macrocyclic antiviral agents

1. A compound represented by Formula (III), or a pharmaceutically acceptable salt thereof:

wherein

m is 1;

n is 1;

X is selected from the group consisting of —CN, —C(O)C(O)NR 13 R 14 , and —C≡R 13 ;

R 1 and R 2 are each independently hydrogen or C 1 -C 6 -alkyl;

R 3 and R 4 are each independently hydrogen or C 1 -C 4 -alkyl;

Z is —CR 21 R 23 -, or Z and the oxygen atom of the carbonyl group are taken together with the carbon atom to which they are attached to form an optionally substituted heteroaryl;

R 21 is selected from the group consisting of hydrogen, halogen, optionally substituted —C 1 -C 6 alkyl, and optionally substituted —C 3 -C 8 cycloalkyl;

R 23 is selected from the group consisting of hydrogen, halogen, —OH, —OR 15 , —OC(O)R 15 , —OC(O)OR 15 , —OC(O)NR 13 R 14 , —NR 13 R 18 , —N 3 , —CN, optionally substituted —C 1 -C 8 alkyl, optionally substituted —C 2 -C 8 alkenyl, optionally substituted —C 2 -C 8 alkynyl, optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;

R 13 and R 14 are independently selected from the group consisting of hydrogen, optionally substituted —C 1 -C 8 alkyl, optionally substituted —C 2 -C 8 alkenyl, optionally substituted —C 2 -C 8 alkynyl, optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl; alternatively R 13 and R 14 are taken together with the nitrogen atom to which they are attached to form an optionally substituted 3- to 8-membered heterocyclic ring;

R 15 is selected from the group consisting of optionally substituted —C 1 -C 8 alkyl, optionally substituted —C 2 -C 8 alkenyl, optionally substituted —C 2 -C 8 alkynyl, optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl;

R 18 is selected from the group consisting of hydrogen, optionally substituted —C 1 -C 8 alkyl, optionally substituted —C 2 -C 8 alkenyl, optionally substituted —C 2 -C 8 alkynyl, optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, —C(O)R 15 , —C(O)OR 15 , —C(O)NR 13 R 14 , —C(O)C(O)NR 13 R 14 , —S(O) 2 R 15 , and —S(O) 2 NR 13 R 14 ; and

R 31 and R 32 are both hydrogen.

2. The compound of claim 1 , wherein Z is

wherein A is selected from the group consisting of —R 15 , —OR 15 , —NR 13 R 14 , and —C(O)NR 3 R 14 ; R 15 is selected from the group consisting of optionally substituted —C 1 -C 8 alkyl, optionally substituted —C 2 -C 8 alkenyl, optionally substituted —C 2 -C 8 alkynyl, optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; and R 13 , R 14 , R 15 , and R 21 are as defined in claim 1 .

3. The compound of claim 1 , represented by Formula (VI-1) or Formula (VI-3), or a pharmaceutically acceptable salt thereof:

wherein R 1 , R 4 , and R 15 are as defined in claim 1 .

4. The compound of claim 1 , selected from the compounds set forth below, or a pharmaceutically acceptable salt thereof:

Compound

Structure

1

2

3

4

5

6

5. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

6. A method of treating a viral infection the method comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

7. The method according to claim 6 , wherein the subject is a human.

8. A method of treating a coronavirus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

9. A method according to claim 8 , wherein the coronavirus is selected from a 229E, NL63, OC43, HKU1, SARS-CoV or a MERS coronavirus.

10. The method according to claim 8 , wherein the compound is administered to the subject orally, subcutaneously, intravenously or by inhalation.

11. A method of inhibiting viral 3C protease or viral 3CL protease in a subject, comprising administering to said subject an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.